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VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients Madel Sadili, MD, FCCP, FPCCP Madel Sadili, MD, FCCP, FPCCP.

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Presentation on theme: "VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients Madel Sadili, MD, FCCP, FPCCP Madel Sadili, MD, FCCP, FPCCP."— Presentation transcript:

1 VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients Madel Sadili, MD, FCCP, FPCCP Madel Sadili, MD, FCCP, FPCCP

2 Lecture Outline  Arterial & Venous Thrombosis  Burden Of Disease (VTE)  Incidence  Rationale for Thromboprophylaxis  Risk Factors  Grading of Recommendations  Recommendations  Drugs  Summary

3 Lecture Outline  Arterial & Venous Thrombosis  Burden Of Disease (VTE)  Incidence  Rationale for Thromboprophylaxis  Risk Factors  Grading of Recommendations  Recommendations  Drugs  Summary

4 Venous Thromboembolism (VTE)  DVT : Deep-vein thrombosis  PE : Pulmonary Embolism

5 Arterial Thrombosis  Most common cause of MI, stroke, & limb gangrene  Usually is initiated by the spontaneous or mechanical rupture of atherosclerotic plaque  Consists of platelet aggregates held together by small amounts of fibrin  Strategies to inhibit arterial thrombogenesis focus mainly on drugs that block platelet function but often include anticoagulant agents to prevent fibrin deposition

6 Venous thrombosis  Leads to PE (can be fatal) & to postphlebitic syndrome  Occurs when procoagulant stimuli overwhelm natural protective mechanisms, ie, excessive activation of coagulation with thrombophilic abnormalities, vessel wall damage or stasis; inflammatory cytokines generated after trauma, surgery, or medical illness activate endothelial cells that express adhesion molecules that attract leukocytes which elaborate tissue factor & express receptors for factor X & fibrinogen, that promotes coagulation on their surfaces; neutrophils generate O2 free radicals & release hydrolytic enzymes, enhancing local clot formation  Venous thrombus is composed mainly of fibrin & RBCs  Anticoagulants are the drugs of choice for their prevention & treatment

7 Lecture Outline  Arterial & Venous Thrombosis  Burden Of Disease (VTE)  Incidence  Rationale for Thromboprophylaxis  Risk Factors  Grading of Recommendations  Recommendations  Drugs  Summary

8 IMPACT OF VENOUS THROMBOEMBOLISM

9 Hospitalization for an acute medical illness  Independently associated with ~8fold increase in relative risk for VTE (Heit, et al. Arch Int Med 2000;160)  10-30% of general medical patients may develop VTE (Cohen, et al. Thromb Haemost 2005; 94)  50-70% of symptomatic thromboembolic events, and 70-80% of fatal PEs occur in non-surgical patients (Goldhaber, et al. Chest 2000; 118)  ¾ of VTE in hospitalized patients occur in acutely ill nonsurgical patients (Leizorovicz, et al. J Thrombosis & Hemostasis 2003)

10  PE (postmortem studies) is associated with up to 10% of deaths in hospitalized patients, and only ¼ of these occur following surgery thus… ¾ of hospitalized patients who suffer a fatal PE are in fact medical patients Cohen et al. Thromb Haemost 2005; 94

11 11 Death 60,000 cases Estimated cost of VTE care = US$ 1.5 billion/year VTE : Magnitude of the Problem Post-thrombotic syndrome 800,000 cases Pulmonary hypertension 30,000 cases Goldhaber SZ et al. Lancet 1999;353:1386–9 DVT 2 million cases PE 600,000 cases

12  Therefore... the appropriate prophylaxis of medical inpatients offers an important opportunity to significantly reduce the burden of disease due to VTE

13 INSTITUTION STUH PGH PHC PGH PERIOD STUDY DESIGN CS DS CC DS NUMBER 1,133 9, AGE ( YEARS ) NB NB - 73 FINDINGS P. Infarct PVO PE / Inf PE / Inf INCIDENCE (%) Samia Reyes Juaneza Pingol Villespin, unpublished, 1994 VENOUS THROMBOEMBOLISM: Philippine AUTOPSY SURVEYS

14 Lecture Outline  Arterial & Venous Thrombosis  Burden Of Disease (VTE)  Incidence  Rationale for Thromboprophylaxis  Risk Factors  Grading of Recommendations  Recommendations  Drugs  Summary

15 Rationale for Thromboprophylaxis in Hospitalized Patients

16 Rationale High Prevalence of VTE Adverse Consequences of unprevented VTE Efficacy & Effectiveness of thromboprophylaxis Description Most hospitalized px have risk factors for VTE DVT is common in many hospitalized px Hosp-acquired DVT & PE are usually clinically silent Difficult to predict which at-risk patients will develop symptomatic thromboembolic complications Screening at-risk px using PE or noninvasive testing is neither effective nor cost-effective Symptomatic DVT & PE Fatal PE Costs of investigating symptomatic patients Risks & costs of treating unprevented VTE, esp bleeding Increased future risk of recurrent VTE Chronic post-thrombotic syndrome Thromboprophylaxis is highly efficacious at preventing DVT, proximal DVT, symptomatic VTE, & fatal PE Prevention of DVT also prevents PE Cost-effectiveness of prophylaxis has repeatedly been demonstrated Geerts, et al. Chest 2001; 119:132S- 175S

17 Lecture Outline  Arterial & Venous Thrombosis  Burden Of Disease (VTE)  Incidence  Rationale for Thromboprophylaxis  Risk Factors  Grading of Recommendations  Recommendations  Drugs  Summary

18 Who are at risk for VTE?

19  Surgery  Trauma (major or lower extremity)  Immobility, paresis  Malignancy  Cancer therapy (hormonal, chemotx, radiotx)  Previous VTE  Increasing age  Pregnancy & the postpartum period  Estrogen-containing oral contraception or HRT  Selective estrogen receptor modulators  Acute medical illness  Heart or respiratory failure  Inflammatory bowel disease  Nephrotic syndrome  Myeloproliferative disease  Paroxysmal nocturnal hemoglobinuria  Obesity  Smoking  Varicose veins  Central venous catheterization  Inherited or acquired thrombophilia Heit, et al. Arch Int Med 2002; 162:

20 Absolute risk of DVT in Hospitalized Patients  Medical px %  General surgery15-40  Major gyne surgery  Major urologic surgery15-40  Neurosurgery15-40  Stroke20-50  Hip or knee arthroplasty; hip fracture surgery40-60  Major trauma40-80  Spinal cord injury60-80  Critical care patients10-80 Geerts, et al. Chest 2001; 119:132S-175S

21  Despite consensus-group recommendations that at-risk medical patients should receive thromboprophylaxis, there is NO CONSENSUS as to which patients are at risk, thus, many patients may not receive appropriate thromboprophylaxis Cohen, et al. Thromb Haemost 2005: 94

22 Cohen, p 9. Fig. 2

23 Samama MM et al. N Engl J Med 1999;341:793–800 Thromboprophylaxis in Acutely Ill Patients MEDENOX (1999) Prophylaxis of VTE in MEDical Patients with ENOXaparin  40mg, 20mg enoxaparin vs placebo OD x 6-14 days  866 patients with heart failure, respiratory, & infectious disease  Primary outcome – VTE between days 1-14 – DVT detected by bilateral venography (or duplex utz) between days 6-14 (or earlier if clinically indicated) or documented PE  Duration of ff-up – 3 months

24 NS = not significant NS P = P = RRR = -63% RRR = -65% Samama MM et al. N Engl J Med 1999;341:793–800 MEDENOX: Incidence of VTE at Day 14

25 MEDENOX  The incidence of VTE was significantly lower in the 40mg enoxaparin group (5.5%) than in the placebo (14.9%)  The benefit was maintained at 3 months

26 PREVENT (2003)  Prospective evaluation of Dalteparin efficacy for the prevention of VTE in immobilized patients  Largest trial (radomized, double-blind, palacebo-controlled) comparing a LMWH with placebo – Dalteparin 5000 IU OD x 14 days  3706 acutely ill medical patients – CHF, acute respiratory failure, or infectious disease  Primary endpoint – clinically important VTE defined as objectively verified symptomatic DVT, PE, sudden death, & objectively verified asymptomatic proximal DVT. Compression UTZ done in all patients who had not reached an endpoint by day 21 Leizorovicz, et al. J Thrombosis & Haemostasis. July 2003

27 PREVENT: Results  Medically ill patients  52% CHF  30% respiratory failure  Also, infection without septic shock, rheumatic disorders, arthritis of the legs, or inflammatory bowel disease P= Leizorovicz A. et al J Thromb Haemost 2003; 1 (Suppl 1):)OC396

28 PREVENT  The incidence of the composite primary outcome was 2.77% in the dalteparin group and 4.96% in the placebo group, a risk reduction of 45%

29 Lecture Outline  Arterial & Venous Thrombosis  Burden Of Disease (VTE)  Incidence  Rationale for Thromboprophylaxis  Risk Factors  Grading of Recommendations  Recommendations  Drugs  Summary

30 Grading of Recommendations

31 Grade Clarity of risk/benefit Methodological strength of supporting evidence Implications 1A Clear RCTs w/o important limitations Strong recommendation; can apply to most patients in most circumstances without reservation 1C+ Clear No RCTs, but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies Strong recommendation; can apply to most patients in most circumstances 1B 1C Clear RCTs with important limitations (inconsistent results, methodological flaws) Observational studies Strong recommendation; likely to apply to most patients Intermediate-strength recommendation; may change when stronger evidence is available

32 Grade Clarity of risk/benefit Methodological strength of supporting evidence Implications 2AUnclear RCTs without important limitations Intermediate-strength recommendation; best action may differ depending on cirumstances or patients’ or societal values 2C+Unclear No RCTs, but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies Weak recommendation; best action may differ depending on circumstances or patients’ or societal values 2BUnclear RCTs with important limitations Weak recommendation; alternative approaches likely to be better for some patients under some circumstances 2CUnclear Observational studiesVery weak recommendation; other alternatives may be equally reasonable

33 Lecture Outline  Arterial & Venous Thrombosis  Burden Of Disease (VTE)  Incidence  Rationale for Thromboprophylaxis  Risk Factors  Grading of Recommendations  Recommendations  Drugs  Summary

34 Recommendations: Thromboprophylaxis in the Medically Ill Geerts, et al. Chest Supplement. Sept 2004; 126/3

35 General Recommendations  It is recommended that mechanical methods of prophylaxis be used primarily in patients who are at high risk of bleeding (Grade 1C+) or as an adjunct to anticoagulant-based prophylaxis (Grade 2A). Careful attention should be directed toward ensuring the proper use of, and optimal compliance with, the mechanical device (Grade 1C+)  We recommend against the use of aspirin alone as prophylaxis against VTE for any patient group (Grade 1A)  For each of the antithrombotic agents, it is recommended that clinicians consider the manufacturer’s suggested dosing guidelines (Grade 1C)

36 General Recommendations  We recommend consideration of renal impairment when deciding on doses of LMWH, fondaparinux, the direct thrombin inhibitors, & other antithrombotic drugs that are cleared by the kidneys, particularly in elderly patients and those who are at high risk for bleeding (Grade 1C+)  In all patients undergoing neuraxial anesthesia or analgesia, special caution when using anticoagulant prophylaxis is recommended (Grade 1C+)

37 Medical Conditions  In acutely ill medical patients who have been admitted to the hospital with CHF or severe respiratory disease, or who are confined to bed & have 1 or more additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, prophylaxis with LDUH or LMWH is recommended (Grade IA)  In medical patients with risk factors for VTE, & in whom there is a contraindication to anticoagulant prophylaxis, the use of mechanical prophylaxis with GCS or IPC is recommended (Grade 1C+)

38 Medical Condition: Acute MI  For all patients at high risk of systemic or venous thromboembolism (anterior MI, pump failure, previous embolus, atrial fibrillation, or LV thrombus), the administration of IV UFH while receiving streptokinase, is recommended (Grade 1C+)

39 Medical Condition: Acute Ischemic Stroke  For acute stroke patients with restricted mobility, prophylactic low-dose subcutaneous heparin or LMWH or heparinoids is recommended (Grade 1A). *Low-dose heparin should be restricted for 24h after administration of thrombolytic therapy; it may be used safely in combination with aspirin.  For patients who have contraindications to anticoagulants, it is recommended that clinicians use intermittent pneumatic compression devices or elastic stockings (Grade 1C)

40 Medical Conditions: Intracerebral Hemorrhage  We recommend the initial use of intermittent pnuematic compression (Grade 1C+).  In stable patients, low-dose SQ heparin may be initiated as soon as the 2 nd day after the onset of the hemorrhage (Grade 2C). Underlying values and preferences: the recommendation for SQ heparin assumes a relatively low degree of risk aversion.

41 Cancer Patients  6-fold increased risk of VTE compared to those without cancer  More specific risk estimates of VTE by cancer type, stage, and treatment approaches are still largely unknown  High among those with malignant brain tumors and adenocarcinoma of the ovary, pancreas, colon, stomach, lung, prostate, and kidney  Cancer patients undergoing surgery have at least 2x the risk of postoperative DVT and more than 3x the risk of fatal PE

42 Cancer Patients  Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A). Refer to the surgical subsections.  Hospitalized cancer patients who are bedridden with an acute medical illness should receive prophylaxis that is appropriate for their current risk state (Grade 1A). Refer to the medical subsection.  It is suggested that clinicians not routinely use prophlaxis to try to prevent thrombosis related to long- term indwelling CVCs in cancer patients (Grade 2B).

43 Critical Care  On admission to a critical care unit, all patients should be assessed for their risk of VTE. Accordingly, most patients should receive thromboprophylaxis (Grade 1A)  For patients who are at high risk for bleeding, mechanical prophylaxis with GCS &/or IPC is recommended, until the bleeding risk decreases (Grade 1C+)  For ICU patients who are at moderate risk for VTE (eg, medically ill or postoperative px), LDUH or LMWH prophylaxis is recommended (Grade 1A)  For patients who are at higher risk, such as that following major trauma or orthopedic surgery, LMWH prophylaxis is recommended (Grade 1A)

44 BURNS  Burn patients with additional risk factors for VTE, including one or more of the ff: advanced age, morbid obesity, extensive or lower extremity burns, concomitant lower extremity trauma, use of a femoral venous catheter, &/or prolonged immobility (Grade 1C+)  If there are no contraindications, the use of either LDUH or LMWH is recommended, starting as soon as it is considered safe to do so (Grade 1C+)

45 Long Distance Travel  For long-distance travelers (ie, flights of >6h duration): avoidance of constrictive clothing around the lower extremities or waist; avoidance of dehydration & frequent calf muscle stretching (Grade 1C)  For long-distance travelers with additional risk factors for VTE, the general strategies listed above are recommended. If active prophylaxis is considered, because of the perceived increased risk of venous thrombosis, the use of properly fitted, below-knee GCS, providing mmHg of pressure at the ankle (Grade 2B), or a single prophylactic dose of LMWH, injected prior to departure (Grade 2B), is recommended.  We recommend against the use of aspirin for VTE prevention associated with travel (Grade 1B)

46 General Surgery Moderate-risk patients:  LDUH 5,000 u bid or LMWH <3,400 u od (Grade 1A) Higher risk patients:  LDUH 5,000 u tid or LMWH >3,400 u od (Grade 1A) High-risk patients with multiple risk factors  Same as high-risk patients plus the use of GCS &/or IPC (Grade 1C+)

47 Major Gynecologic & Urologic Surgery  LDUH 5,000u bid to tid (Grade 1A)

48 Orthopedic Surgery Elective total hip or knee arthroplasty:  LMWH, Fondaparinux, or adjusted-dose vit K antagonist (VKA with INR 2-3 (Grade 1A) Hip fracture surgery (HFS):  Fondaparinux (Grade 1A), LMWH (Grade 1C+), VKA (Grade 2B), or LDUH (Grade 1B) Thromboprophylaxis is recommended to be given for at least 10 days (Grade 1A)

49 Increased Risk of Bleeding  Recent surgery  Known bleeding disorder  Impaired renal function  Uncontrolled hypertension  Large ischaemic cerebral infarction  Active GI bleeding (peptic/bowel)  Use of antiplatelet drugs or NSAIDs

50 Lecture Outline  Arterial & Venous Thrombosis  Burden Of Disease (VTE)  Incidence  Rationale for Thromboprophylaxis  Risk Factors  Grading of Recommendations  Recommendations  Drugs  Summary

51 Methods of DVT Prophylaxis  Unfractionated heparin (UFH)  Low-molecular-weight heparins (LMWHs)  Oral anticoagulants (warfarin)  Pentasaccharides (fondaparinux)  Antiplatelet therapy  Mechanical compression and early ambulation

52 Unfractionated Heparin  Main anticoagulant action is mediated by the heparin/AT interaction, which inactivates thrombin factor IIa & factors Xa, IXa, & XIIa  Increases vessel wall permeability, suppresses proliferation of vascular smooth muscle cells, suppresses osteoblast formation, & activates osteoclasts, promoting bone loss, & HIT  IV infusion or SC injection (reduced bioavailabiltiy, thus, 10% higher initial dose)  Dose adjustment by monitoring aPTT, or, when very high doses are given, by ACT (activated clotting time)

53 LMWH  Polysulfated glycosaminoglycans about 1/3 the molecular weight of UFH  Like heparin, major anticoagulant effect by activating AT  Administered in fixed doses, for thromboprophylaxis, or in total body weight (TBW)-adjusted doses, for therapeutic effect

54 LMWH  Reduced binding properties to proteins & cells, explaining all of the anticoagulant, phramacokinetic, & other biological differences between heparin & LMWH: -reduced ability to inactivate thrombin bec the smaller fragments cannot bind simultaneously to AT & thrombin, but, since bridging bet AT & factor Xa is less critical for factor Xa activity, the smaller fragments inactivate factor Xa almost as well as larger molecules -reduced binding to plasma proteins is responsible for the more predictable dose-response relationship of LMWHs -lower binding to macrophages & endothelial cells increases the plasma half-life of LMWHs -reduced binding to platelets & PF4 explains lower incidence of HIT -reduced binding to osteoblasts results in lower incidence of bone loss

55 Fondaparinux  New parenteral indirect factor Xa inhibitor, with no activity against thrombin  Excellent bioavailability after SQ injection with a plasma half-life of 17h, thus given OD  Does not bind to platelets or PF4 (no heparin/PF4 complex), thus, no HIT  Phase III trial for thromboprophylaxis at 2.5mg OD

56 EnoxaparinUFH Patients with heart failure Patients (%) Kleber FX et al. Am Heart J 2003;145:614–21 THE-PRINCE Study: Incidence of VTE with Enoxaparin and UFH Thromboembolism Prevention in Heart Failure or Severe Respiratory Disease with Enoxaparin (THE-PRINCE) P= EnoxaparinUFH Patients (%) P= All evaluable patients

57 VTE Prevention Non-Pharmacologic Methods  Ambulation  Elastic or Graduated compression stockings (GCS)  Intermittent pneumatic compression (IPC) devices  Arteriovenous foot pumps (VFP)

58 Mechanical Methods of Prophylaxis  Increase venous outflow and/or reduce stasis within the leg veins  Primary attraction is the lack of bleeding potential, therefore, are considered for patients with high bleeding risks  Must select the correct size of the device, must properly apply them, and must ensure that they are removed for only a short time each day, and that they do not impede ambulation

59 Recommendation: Mechanical Methods of Prophylaxis  Should be used primarily in patients who are at high risk of bleeding (Grade 1C+), or an an adjunct to anticoagulant-based prophylaxis (Grade 2A)  Careful attention must be directed toward ensuring the proper use of, and optimal compliance with, the mechanical device (Grace 1C+)

60 Summary  VTE is an important clinical problem worldwide  Thromboprophylaxis for the medically-ill patients who are at risk for VTE is effective & safe  The concensus recommends against the use of aspirin alone for thromoprophylaxis  LDUH, LMWH, VKA, Fondaparinux, and mechanical devices are recommended for thromboprophylaxis.

61 Thromboprophylaxis in Internal Medicine: a Meta-analysis  19,764 patients  UFH or LMWH versus control

62 Thromboprophylaxis in Internal Medicine: LMWH vs. UFH  4,469 patients  LMWH vs. UFH

63 *Includes randomized trials in which routine screening with an objective diagnostic test for DVT was used General Medical Patients: LDUH Versus No Prophylaxis* 1.6 (1/64)10.4 (7/67)b.i.d.PlaceboCade (2/50)26.0 (13/50)t.i.d.No prophylaxisBelch et al (1/38) 22.5 (9/40) t.i.d.No prophylaxisGallus et al LDUHControlLDUHControl DVT, % (n/N)Intervention Study b.i.d., twice a day; t.i.d., 3 times a day Gallus AS et al. N Engl J Med 1973;288:545–51 Belch JJ et al. Scott J Med 1981;26:115–7 Cade JF. Crit Care Med 1982;10:448–50

64 Bergmann & Neuhart 1996 Harenberg et al Lechler et al ,000 IU b.i.d. 5,000 IU t.i.d. 5,000 IU t.i.d. Enoxaparin 20 mg o.d. Nadroparin 36 mg o.d. Enoxaparin 40 mg o.d. 4.6 (10/216) 0.5 (4/780) 1.4 (6/443) 4.8 (10/207) 0.7 (6/810) 0.2 (1/442) *Includes randomized trials in which LDUH and LMWH were compared and routine screening with an objective diagnostic test for DVT was used General Medical Patients: LDUH Versus LMWH* (1) LMWHLDUH LMWH LDUH DVT, % (n/N)Intervention Study Bergmann J-F & Neuhart E. Thromb Haemost 1996;76:529–34 Harenberg J et al. Haemostasis 1996;26:127–39 Lechler E et al. Haemostasis 1996;26(Suppl 2):49–56

65 Harenberg et al † Kleber et al ,000 IU t.i.d. 5,000 IU t.i.d. Enoxaparin 40 mg o.d. Enoxaparin 40 mg o.d (67/303) 10.4 (22/212) 15.6 (51/327) 8.4 (20/239) *Includes randomized trials in which LDUH and LMWH were compared and routine screening with an objective diagnostic test for DVT was used † This study has been presented only in abstract form to date General Medical Patients: LDUH Versus LMWH* (2) LMWHLDUH LMWH LDUH DVT, % (n/N)Intervention Study Harenberg J et al. Blood 1999;94(Suppl 1):399A Kleber FX et al. Am Heart J 2003;145:614–21

66 RR=0.43 (95% CI, 0.37–0.50) RR of DVT in studies comparing heparins with no treatment Surgery General medicine Stroke Acute MI n=12,550 n=845 RR=0.44 (95% CI, 0.29–0.64) n=791 RR=0.43 (95% CI, 0.26–0.73) n=659 RR=0.32 (95% CI, 0.20–0.61) CI, confidence interval; MI, myocardial infarction Prophylaxis of VTE in Medical Patients Heparin betterHeparin worse RR

67 Thromboprophylaxis in Internal Medicine: Risk:Benefit Ratio  Risk:benefit ratio of heparins vs. controls  50% reduction in risk of symptomatic PE  2-fold increase in major bleeding  Risk:benefit ratio of LMWH versus UFH  Similar effect on symptomatic PE  50% reduction in risk of major bleeding  LMWHs are effective and safe

68 MEDENOX Placebo (n=96) MEDENOX Enoxaparin 40 mg o.d. (n=98) THE-PRINCE Enoxaparin 40 mg o.d. (n=113) THE-PRINCE UFH 5,000 IU t.i.d. (n=93) Incidence of VTE (%) UFH, unfractionated heparin Kleber FX et al. Am Heart J 2003;145:614–21 Samama MM et al. N Engl J Med 1999;341:793–800 Incidence of VTE in Heart Failure Patients in THE-PRINCE and MEDENOX studies

69 PREVENT: Study Design  Dalteparin vs. Placebo in medically ill patients (n=3,706)  Primary endpoint: reduction in clinically important VTE  Objectively verified symptomatic DVT  Objectively verified asymptomatic proximal DVT  Fatal and non-fatal PE  Sudden death  Selection of Patients: Day 3  Randomizations: Day 1  Bilateral ultrasonography Treatment Period  Follow-up period PREVENT, Prospective Evaluation of Dalteparin Efficacy In Immobilized Patients Trial Vaitkus PT et al Vasc Med 2002;7:269-73

70 Leizorovicz A et al. J Thromb Haemost 2003;1(Suppl 1):OC396 P= (Cochran-Mantel-Haenszel test) PREVENT: Incidence of VTE on Day 21 Incidence of VTE (%) D ifference in Risk Dalteparin Placebo incidence ratio (n=1,518) (n=1,473) (–3.57 to –0.81) (0.38–0.80)

71 EXCLAIM: Extended Clinical Prophylaxis in Acutely ill Medical Patients

72 Thromboprophylaxis in Medical Patients: Real World Data  DVT Free  Routine preventive efforts among inpatients are not widely practiced, especially among acutely ill medical patients  IMPROVE 2  International Medical Prevention Registry on Venous Thromboembolism  Most acutely ill medical patients do not receive thromboprophylaxis during hospitalization Goldhaber SZ & Tapson VF. J Thromb Haemost 2003; 1 (Suppl 1):P1470 Anderson FA et al. J Thromb Haemost 2003; 1 (Suppl 1):P1438

73 DVT FREE Registry (1)  Of the 5,451 patients, 50% (n=2,725) were diagnosed with DVT as outpatients or in the emergency department and 50% (n=2,726) were diagnosed as inpatients  Overall, 71% (n=3,894) of patients received no prophylaxis for DVT within 30 days prior to diagnosis  Of the 29% (n=1,557) of patients who did receive prophylaxis, 30% (n=410) were diagnosed with DVT as outpatients and 70% (n=1,147) as inpatients Goldhaber SZ & Tapson VF. J Thromb Haemost 2003;1(Suppl 1):P1470

74 DVT FREE Registry (2)  Surgical patients (those with a history of surgery within 3 months prior to diagnosis) were far more likely to receive DVT prophylaxis than non-surgical patients  The vast majority of non-surgical patients (80%; n=2,295) received no prophylaxis within 30 days before diagnosis Goldhaber SZ & Tapson VF. J Thromb Haemost 2003;1(Suppl 1):P1470

75 IMPROVE: Prophylaxis According to Primary-admission Category Cardiac (n=254) Pulmonary (n=348) Neurological (n=208) Cancer (n=104) Patients receiving thromboprophylaxis (%) Primary-admission category

76 IMPROVE: Prophylaxis According to Number of Risk Factors (n=86) 1–2 (n=826) 3–4 (n=605)  5 (n=77) Number of VTE risk factors Patients receiving thromboprophylaxis (%)

77 RR=0.44 (0.29–0.64)P<0.001 RR=0.48 (0.34–0.68)P<0.001 P=NS Mismetti P et al. Thromb Haemost 2000;83:14–19 Thromboprophylaxis in Medical Patients: Heparins (UFH and LMWH) versus Control DVT PE Death Major haemorrhage Heparins better Heparins worse RR

78 P=NS RR=0.48 (0.23–1.0) Thromboprophylaxis in Medical Patients: LMWH versus UFH Mismetti P et al. Thromb Haemost 2000;83:14–19 DVT PE Death Major haemorrhage LMWH better UFH better RR P=0.049

79 SAFETY of THROMBOPROPHYLAXIS

80 MEDENOX: Summary of haemorrhage during the treatment period n = 27 n = 36 n = 34 n = 5 n = 4 n = 1 n = 4 n = 6 NS NS = not significant Placebo Enoxaparin 20 mgEnoxaparin 40 mg

81 UFH Overall adverse eventsInjection-site haematoma UFH P<0.004 P<0.027 Patients (%) THE-PRINCE Study: Adverse-event Analysis Kleber FX et al. Am Heart J 2003;145:614–21 Enoxaparin

82 Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398 RIETE: Does VTE Outcome Differ in Surgical and Medical Patients?  RIETE: computerized registry of patients with VTE  Consecutive, current and symptomatic VTE  3-month outcome SurgicalMedical (n=672)(n=1,286) Thromboprophylaxis 454 (68%)312 (24%)

83 RIETE: VTE Characteristics SurgicalMedicalP value (n=671)(n=1,286) Distal DVT 117 (17%) 115 (9%)0.001 Proximal DVT295 (44%)645 (50%)0.009 PE259 (39%)526 (41%)NS Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398

84 Death Fatal PE Fatal bleeding Major bleeding RIETE: Major Outcomes at 3 Months Odds ratio (95% CI) 0.36 (0.25–0.51) 0.22 (0.08–0.58) 0.11 (0.01–0.79) 0.36 (0.17–0.74) Surgical (n=671) 46 (7%) 5 (0.8%) 1 (0.1%) 10 (1.5%) Medical (n=1,286) 218 (17%) 43 (3.3%) 17 (1.3%) 52 (4.0%) P value Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398

85 ADR, adverse drug reaction Safety of LMWHs in Medical Patients Hemorrhage  Anecdotal reports of ADRs induced by LMWHs  In 1997, two cases of fatal bleeding were reported (cancer in one case, morbid obesity and cardiac failure in the other). Patients were over 80 years with worsening renal insufficiency (Hôtel Dieu, Paris, France)  Increased bleeding in cardiac patients in trials with a high dose of enoxaparin

86 Safety of Enoxaparin Pooled analysis of THE-PRINCE, PRIME and MEDENOX studies Placebo n (%) UFH 5,000 IU TID n(%) Enoxaparin 40 mg OD n (%) Total 362 (100)815 (100)1,169 (100) Major bleeding* 4 (1.1)8 (1.0)9 (0.8) Minor bleeding^ 27 (7.5)105 (12.9)89 (7.6) Thrombocytopenia § 3 (0.8)5 (0.6)5 (0.4) *UFH vs. placebo: RR=1.73 (95% CI, ); P=0.009 ^Enoxaparin vs. Placebo: RR=1.02 (95% CI, ); P=NS § Enoxparin vs. UFH: RR= 0.59 (95% CI, ); P= Alikhan R. & Cohen AT. Thromb Haemost 2003;89:590-1

87 Tolerability of LMWHs: Bleeding Events  Patients from medical departments: cardiology, geriatrics, angiology, infectious disease  More than 50% of patients received aspirin  Prolonged treatment of more than 10 days in 27% of patients  Bleeding events observed in 15/334 (4.7%) of patients  7 (7%) during curative treatment  8 (3.4%) during thromboprophylaxis  increased bleeding risk when creatinine clearance <20 ml/min Digestive hemorrhage3Haematoma7 Ecchymoses2Epistaxis1 Gingival bleeding 2  13 cases of thrombocytosis, 4 moderate thrombocytopenia, 1 hepatic cytosis (doubtful causal relationship) Cestac P et al. Drug Saf 2003;26:197–207

88 LMWHs: Safe and Cost- effective  The good safety profile of LMWHs is an important characteristic of these drugs which allows wide international use and substitution for UFH in most clinical indications Success factor  Socio-economic studies have concluded that LMWHs are cost-effective1,2  MEDENOX trial: for patients in a tertiary-care setting, incremental cost-effectiveness of enoxaparin 40 mg versus placebo was US$ 87/VTE avoided1 1 Lamy A et al. Can Respir J 2002;9:169–77 2 de Lissovoy G & Subedi P. Am J Manag Care 2002;8:1082–8

89 FDA Approved Indications for Currently Available LMWH IndicationEnoxaparinDalteparinTinzaparin Prevention of DVT in Hip Replacement Yes No Extended ProphylaxisYes No Prevention of DVT in Knee ReplacementYesNo Prevention of DVT in Abdominal SurgeryYes No Inpatient treatment of DVT w/wo PEYesNoYes Outpatient treatment of DVT w/o PEYesNo?? Prevention of Ischemia in UA/NSTEMIYes No Prevention of DVT in Medically IllYesNo

90 SUMMARY and RECOMMENDATIONS


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